The long-term goal of this program grant is to optimize the use of hyperthermia (HT) with radiotherapy (RT) and/or chemotherapy (CTx) to improve local tumor control, disease free and overall survival for patients with locally advanced cancers that are not effectively treated with best conventional therapy. Prior strengths of the program have been the emphases on thermal dosimetry, interrelationships between HT and tumor physiology and use of HT to augment liposomal drug delivery. New clinical trials continue and expand the themes to: (1) develop non-invasive thermometry, (2) examine HT combined with liposomal drugs, particularly with novel thermolabile liposomes that release contents within seconds of reaching their phase transition temperature, (3) conduct phase III trials comparing best conventional therapy q HT, (4) examine whether pathophysiology and/or gene expression patterns obtained prior to and during therapy predict for treatment outcome. A multidisciplinary approach includes experts in radiation and medical oncology, biostatistics, radiology, pathology, surgery, cancer biology, physiology, genetics, hyperthermia physics and engineering and materials science to approach the four themes. Project 1 will develop MR-based non-invasive thermometry in tumors of extremities, breast and pelvis/abdomen using fully integrated MR compatible RF heating devices. Project 2 will develop models to facilitate real-time power control during HT using non-invasive thermometry as feedback. Project 3 will use novel MR-imageable thermolabile doxorubicin containing liposomes to compare anti-tumor effects of different drug dose "painting" protocols and test the potential of a cisplatin thermolabile liposome to overcome cisplatin resistance and/or interact positively with RT. Project 4 will examine the relationship between thermal dose fractionation, tumor physiologic change and treatment outcome in dogs with spontaneous soft tissue sarcomas treated with fractionated RT. Project 5 has five clinical trials aimed toward conducting: (1) non-invasive thermometry in soft tissue sarcomas and extremity melanomas treated with infusional chemotherapy, (2) a multi-institutional phase III trial testing CTx+RT+/- HT in patients with locally advanced cervix cancer, (3) phase l/ll trials testing HT + non-thermally sensitive and thermolabile doxorubicin containing liposomes for locally advanced breast cancer. (4) The role of tumor physiology and gene expression patterns in controlling treatment outcome threads thoughout the program. Four cores (Administrative, Biostatistics, Tissue, Imaging / Engineering) support the program.